Oxidative Stress and Nrf2 Signaling Role in Oral Squamous Cell Carcinoma: A Double‐Edged Sword

BACKGROUND: Oxidative stress has a significant role in the origination and progression of oral squamous cell carcinoma (OSCC) by interrupting cellular redox homeostasis and gene regulation. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is a major regulator of antioxidant defense, activating cytoprotective genes under stress conditions. AIM: The study highlight the dual role of the Kelch-like ECH-associated protein-1 (Keap1)/Nrf2 signaling pathway in the development, progression, and therapeutic resistance of OSCC. METHODOLOGY: Literature was conducted to evaluate the role of oxidative stress and Keap1/Nrf2 signaling in OSCC. RESULTS: Nrf2 protects normal cells from oxidative damage, its persistent activation in cancer cells promotes tumor progression, metabolic reprogramming, and resistance to chemotherapy and radiotherapy. Dysregulation of the Keap1/Nrf2 axis enhances cancer cell survival and contributes to radioresistance in OSCC. However, Nrf2 displays a dual function as both a tumor suppressor and promoter. CONCLUSION: The Keap1/Nrf2 signaling pathway plays a key role in OSCC pathogenesis and treatment resistance. Targeting the Keap1/Nrf2 signaling pathway may provide a promising therapeutic strategy to overcome treatment resistance in OSCC.